Michael R. Trimble MD
Professor of Behavioral Neurology, Department of Neurology, Institute of Neurology, London, United Kingdom
There is a considerable literature on the use of antiepileptic drugs for the management of psychiatric disorders; an introduction to this subject is given in Chapter 25. It was therefore to be expected with the introduction of oxcarbazepine, which has a clinical profile similar to that of carbamazepine, that it, too, would be tried in the management of disorders other than epilepsy, particularly for psychiatric syndromes.
The investigations with oxcarbazepine were carried out mainly over a decade ago, and there are few trials from which to draw any conclusions. However, this is a review of the published data, and most of the research has been conducted in patients with affective disorders.
CLINICAL TRIALS OF OXCARBAZEPINE IN AFFECTIVE DISORDERS
The studies reviewed here are all summarized in Table 48.1.
The first study was that of Emrich et al. (1). The effects of sodium valproate were compared with the effects of oxcarbazepine, and all patients were said to have a maniform psychosis. The design was double-blind, placebo-controlled trial with an A-B-A design. The evaluations were carried out using the In-patient Multi-dimensional Psychiatric Scale (IMPS), and all patients had clinical evaluations. The doses of oxcarbazepine were 1,800 to 2,100 mg/day, and at the end of an unspecified treatment period, a 49.9% improvement in the IMPS score was recorded.
Based on the relative success of this pilot investigation, Emrich presented data on a more extended multicenter trial of 42 patients with acute mania, oxcarbazepine (n = 19) being compared with haloperidol (2). The data from this study are shown in Figure 48.1. Although initially the improvements seemed to be more rapid with haloperidol, after 2 weeks the results with both drugs were comparable. The dose of oxcarbazepine was increased during the course of the study, the mean dose being 2.4 g/day. The equivalent dose of haloperidol was 15 mg. Ten percent of patients taking oxcarbazepine experienced unwanted effects, in comparison with 35% of those taking haloperidol. The Physicians' Global Rating Scale over the treatment course was good to excellent for carbamazepine in 94% of those studied in comparison with 83% taking haloperidol. It was moderate to poor in five patients receiving haloperidol and only one patient taking oxcarbazepine.
In a further study, 28 patients receiving oxcarbazepine were compared with 24 receiving lithium over a similar time course. After 2 weeks, there was no difference in the response rate. In this study, a lower dose of oxcarbazepine was reached (1.4 g/day), the mean dose of lithium being 1.1 g. When comparing adverse effects, 28% of patients receiving oxcarbazepine and 18.5% of patients taking lithium reported such effects; however, the tolerability according to the Physician's Global Evaluation was the same for both drugs. An excellent or good response to oxcarbazepine was reported in 93% of cases, compared with 92% in patients taking lithium. There were 3.4% poor responders with oxcarbazepine and 8.3% with lithium. From these data, the authors concluded that oxcarbazepine was as effective as lithium in the management of acute mania and had some advantage with regard to tolerability.
Mueller et al. (3) pointed out that the tolerability of oxcarbazepine was good, and it was better in comparison with carbamazepine in patients with epilepsy or trigeminal neuralgia. These investigators performed a trial in patients with acute mania. This was an open study of 48 patients treated for 10 to 86 days. The doses varied between 600 and 1,800 mg/day, and 83% of patients were said to have had a very good response.
TABLE 48.1. STUDIES OF OXCARBAZEPINE IN AFFECTIVE DISORDERS
These investigators then carried out a double-blind study of oxcarbazepine (900 to 1,200 mg/day), comparing it with haloperidol (15 to 20 mg/day), with 10 patients in each group. The change in mood was rated using the Bech-Rafaelson Mania Scale. The results were equivalent, with a slightly faster onset of action in the oxcarbazepine-treated group. The authors considered carbamazepine and oxcarbazepine to be effective for the treatment of acute mania, but they considered that oxcarbazepine would be better tolerated. They specified the antimanic action of oxcarbazepine as not one of sedation, but rather suggested a more direct action on psychopathologic symptoms.
Prophylaxis of Bipolar Disorders
There are even fewer studies of oxcarbazepine in the longerterm management of bipolar disorders than the acute studies or the data on carbamazepine. An early study was carried out by Greil et al. (4). These investigators conducted an open pilot study on nine patients and commented on the good tolerability of oxcarbazepine in doses up to 1,200 mg/day, but they were unable to say anything about the clinical effectiveness of the drug.
FIGURE 48.1. Oxcarbazepine in acute mania. Mean mania rating scale values during 15 days of therapy using oxcarbazepine or haloperidol in 19 manic patients in each group. (Rating according to Bech P, Bolung TG, Kramp P, et al. The Bech-Rafaelson mania scale and the Hamilton depression scale. Acta Psychiatric Scandanavica 1979;59: 420-430.) [From Emrich HM. Studies with oxcarbazepine in acute mania. Int Clin Psychopharmacol 1990;5(Suppl 1):83-88, with permission.]
Wildgrube (5) incorporated 18 patients with a diagnosis of bipolar affective disorders, unipolar mania, or schizoaffective psychoses into a study randomly allocating them to lithium or oxcarbazepine; another five patients were treated with oxcarbazepine after unsatisfactory treatment with lithium. During the course of the trial, the dose of oxcarbazepine was increased to a maximum of 2,400 mg/day. The patients were rated using the Bech-Rafaelson Rating Scale, and the maximum period of observation in this study was 2 years and 9 months.
From the initial group, the results of eight patients taking oxcarbazepine and of seven taking lithium were compared. The lithium-treated patients were younger (mean age, 31 years) than the oxcarbazepine-treated patients (mean age, 44 years). Further, the oxcarbazepine-treated patients had a longer history of bipolar disorder than did the patients who were taking lithium. As noted, some of the oxcarbazepine-treated patients were lithium nonresponders.
The study proved disappointing, in that six of nine oxcarbazepine-treated patients and three of nine lithium-treated patients dropped out of the study. The conclusion, noting the number of manic and depressive relapses in patients, was that oxcarbazepine was less effective than
lithium, although the problem with patient recruitment and dropout was obvious, and few reliable conclusions could be drawn.
Cabrera et al. (6) compared the prophylactic effects of oxcarbazepine and lithium; two small groups were tested. One was randomized, and the other was nonrandomized. Essentially fewer episodes of affective disorder were seen after the initiation of oxcarbazepine, when compared with before. In comparison with lithium, fewer adverse reactions occurred.
OXCARBAZEPINE IN OTHER PSYCHIATRIC DISORDERS
The only other population examined with oxcarbazepine comprised patients with aggressive disorders, but the results of these trials have not been published in full. Vartiainen et al. (7) studied 16 chronically psychotic patients who had been receiving carbamazepine for aggressive behavior. This was a 16-week open study, and the patients were given carbamazepine for 8 weeks, followed by the oxcarbazepine substitution. The clinical state was measured using the Global Aggression Scale. These investigators reported that the antiaggressive effects of the oxcarbazepine and carbamazepine were equivalent, but they noted that oxcarbazepine had fewer side effects. Concomitant haloperidol, which was also being prescribed, led to an increase in serum levels of oxcarbazepine in two patients.
The data on the effects of oxcarbazepine on psychopathology are limited. There are no studies in patients with epilepsy in which mood has been monitored, and the few studies in psychiatric patients are mostly in acute mania. However, it is known form the studies on epilepsy (Chapter 47), that oxcarbazepine is well tolerated, better so than carbamazepine, and it seems likely that this favorable profile would have benefit for patients with psychopathology, irrespective of whether they have epilepsy.
In the studies reviewed here, >80% of the patients given oxcarbazepine for affective disorders were reported to have a favorable response, and this finding compares well with lithium comparisons (~55% to 80%). Further studies are needed to clarify the role of oxcarbazepine for prophylaxis of bipolar disorder and to establish its utility for some other conditions in which carbamazepine has been shown to be of value, such as schizoaffective disorder and a variety of aggressive syndromes.